Benzazepinone derivatives

ABSTRACT

The invention relates to substituted 3-amino-1-arylalkyl-benzazepin-2-ones of the general formula ##STR1## wherein Ar is aryl; 
     X is --O-- or --S(O) n  -- and n is 0, 1 or 2; 
     X 1  is C 1  -C 2  alkylene or a direct bond; 
     R 1  is hydrogen, lower alkyl, aryl-lower alkyl or acyl; 
     R 2  is lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkoxy-lower alkyl, aryl-lower alkyl or C 3  -C 7  cycloalkyl-lower alkyl; 
     R 3  is carboxy; lower alkoxycarbonyl; lower alkoxy-lower alkoxycarbonyl; aryl-lower alkoxycarbonyl; aryloxycarbonyl; carbamoyl; carbamoyl that (i) is monosubstituted by hydroxy, lower alkanesulfonyl, halo-lower alkanesulfonyl or by arylsulfonyl, (ii) is monosubstituted or disubstituted, the substituents being independent of one another, by lower alkyl, lower alkenyl, lower alkynyl or by phenyl-lower alkyl or (iii) is disubstituted by lower alkylene or by lower alkylene-Z 1  -lower alkylene, Z 1  being O, S or NH; 5-tetrazolyl; PO 2  H 2  ; PO 3  H 2  or SO 3  H 2  ; the ring A and aromatic radicals are, independently of one another, unsubstituted or mono- or poly-substituted by substituents selected from the group consisting of: lower alkyl, aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-lower alkoxy, C 3  -C 7  cycloalkyl, C 3  -C 7  cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino and amino that is monosubstituted or disubstituted, the substituents being independent of one another, by lower alkyl, aryl-lower alkyl or by aryl, or disubstituted by lower alkylene or by lower alkyleneoxy-lower alkylene; 
     or a salt thereof; to processes for the preparation thereof; and to the use thereof as well as to pharmaceutical compositions that comprise compounds of formula (I) or pharmaceutically acceptable salts thereof.

The invention relates to substituted3-amino-1-arylalkyl-benzazepin-2-ones of the general formula ##STR2##wherein Ar is aryl;

X is --O-- or --S(O)_(n) -- and n is 0, 1 or 2;

X₁ is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, lower alkyl, aryl-lower alkyl or acyl;

R₂ is lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,aryl-lower alkoxy-lower alkyl, aryl-lower alkyl or C₃ -C₇cycloalkyl-lower alkyl;

R₃ is carboxy; lower alkoxycarbonyl; lower alkoxy-lower alkoxycarbonyl;aryl-lower alkoxycarbonyl; aryloxycarbonyl; carbamoyl; carbamoyl that(i) is monosubstituted by hydroxy, lower alkanesulfonyl, halo-loweralkanesulfonyl or by arylsulfonyl, (ii) is monosubstituted ordisubstituted, the substituents being independent of one another, bylower alkyl, lower alkenyl, lower alkynyl or by phenyl-lower alkyl or(iii) is disubstituted by lower alkylene or by lower alkylene-Z₁ -loweralkylene, Z₁ being O, S or NH; 5-tetrazolyl; PO₂ H₂ ; PO₃ H₂ or SO₃ H₂ ;

the ring A and aromatic radicals are, independently of one another,unsubstituted or mono- or poly-substituted by substituents selected fromthe group consisting of: lower alkyl, aryl-lower alkyl, loweralkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-loweralkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl, nitro,halogen, trifluoromethyl, amino and amino that is monosubstituted ordisubstituted, the substituents being independent of one another, bylower alkyl, aryl-lower alkyl or by aryl, or disubstituted by loweralkylene or by lower alkyleneoxy-lower alkylene;

or salts thereof; to processes for the preparation thereof; and to theuse thereof as well as to pharmaceutical compositions that comprisecompounds of formula (I) or pharmaceutically acceptable salts thereof.

There are described in the literature two receptor sub-types [AT₁ andAT₂ ] of angiotensin(II) which differ in respect of their differentaffinities for synthetic angiotensin-II analogues.

AT₂ -receptors can be identified in various body tissues. Such receptorsare described in the relevant literature as being expressed, forexample, in neuron tumour cells, in transformed neural cells, in variousregions of the central nervous system, in the heart and the arteries, infemale reproductive organs, such as the uterus and the ovaries, in theadrenal glands and the pancreas and also in healing skin.

Surprisingly, the compounds of the present invention exhibit selectivebinding to the angiotensin-II-AT₂ -receptor in the model described byWhitebread et al., Biochem. Biophys. Res. Comm. 1989, 163, 184-191.Those binding properties of the compounds according to the inventionwere detected below a concentration of 50 μmol/l. Accordingly, thecompounds according to the invention may be used especially in theprophylactic or therapeutic treatment of symptoms that are caused by AT₂-receptors.

It has been demonstrated that an AT₂ -receptor stimulation

modulates the protein tyrosine phosphatase in the rat phaeochromocytomacell line PC12W and in AT₂ -receptor transfected COS cells [Botari etal. Biochem. Biophys. Res. Commun. 1992, 183, 206-211; Botari et al.,Front. Neuroendocrinol. 1993, 44, 207-213; Brechler et al., Regul.Peptide 1993, 44, 207-213; Kambayashi et al., J. Biol. Chem. 1993, 268,24543-24546]

inhibits the guanylate cyclase in PC12W and neuron cultures [Botari etal., Biochem. Biophys. Res. Commun. 1992, 183, 206-211; Botari et al.,Front, Neuroendocrinol, 1993, 44, 207-213; Brechler et al., Regul.Peptide 1993, 44, 207-213: Summers et al., Am. J. Physiol. 1991, 260,679-687; Summers et al., Proc. Natl. Acad. Sci. USA 1991, 88, 7567-7571]and

modulates T-type Ca⁺⁺ flows in neuroblastoma NG108-15 cells [Buisson etal., FEBS 1992, 309, 161-164].

In addition, the AT₂ -receptor is involved in cell growth and cellproliferation, since it is especially expressed in high density duringfoetal development [Grady et al., J. Clin. Invest. 1991, 88 921-933].

As a result of the ability of AT₂ -ligands to inhibit the proliferationof vascular endothelial cells, and since endothelial cell proliferationis the cause of angiogenesis, which is in turn a prerequisite for tumourgrowth and the development of metastases, the compounds according to theinvention may be used in the treatment of cancer and those disordersgenerally associated with benign and malignant proliferation.

AT₂ -receptors also bring about the modulation of phosphotyrosinephosphatase activity (PTPase activity), which is associated withgrowth-inhibiting and antiproliferative effects. AT₂ -receptors areexpressed in vascular smooth muscle cells during neointimal development.The compounds according to the invention may therefore be used in thetreatment of vascular proliferation disorders, including vascular cellwall hypertrophy, which follows a thrombosis, angioplasty, Buerger'sdisease, atherosclerosis and arteriosclerosis.

The modulation of PTPase activity also plays a part in connection withthe action of insulin, which is mediated by a tyrosine kinase receptorand a signal pathway for the tyrosine-phosphorylation/dephosphorylationenzyme system. Accordingly, the compounds according to the invention mayalso be used in the treatment of diabetic disorders and complications,including diabetic neuropathy, nephropathy and vasculopathy.

AT₂ -receptors also regulate the diameter of cerebral arteries and thuscerebral blood flow, and are thus suitable for the treatment of cerebralischaemia and strokes and associated symptoms.

A further important field of treatment arises from the fact that AT₂-receptors are localised in selective areas of the brain that areassociated with the control of motor activity, of sensory and visualphenomena and of the limbic system, and with the regulation of appetite.Similarly, calcium flows, which are associated with the control ofneurosecretion and electrical activity, are modulated by AT₂ -receptors.Accordingly, the compounds according to the invention may be used in thetreatment and diagnosis of numerous neurological, psychiatric,neuroendocrinal, neurodegenerative and neuroimmunological disorders,including disorders associated with dependency, anxiety states,depression, epilepsy, memory, psychoses, pain, sleep, tardivedyskinesia, hyperactivity and Petit Mal, and disorders associated withthe regulation of autonomous functions, and also in the treatment ofParkinson's disease, Alzheimer's disease and appetite disorders andassociated phenomena, such as obesity and anorexia.

Since, as mentioned, AT₂ -receptors influence PTPase activity, and suchreceptors have also been identified in healing skin, the compoundsaccording to the invention can also modulate cell growth and thedifferentiation of the skin and play a part in the reorganisation ofskin tissue, thereby promoting the healing of wounds and preventingkeloid formation. AT₂ -receptors that exert a regulatory effect onovulation have also been found in ovarian follicle cells. To that extentthe compounds according to the invention may be used to treat sterilitythat has been caused by anovulation, ovulation disorders, dysfunction ofthe corpus luteum, missed abortion and also other such disorders thatare associated with ovary dysfunction, including premenstrual syndromeand dysmenorrhoea.

There is a high density of AT₂ -receptors in the human myometrium. As aresult of the stimulation of PTPase activity, contraction of the uteruscan be inhibited, and the compounds according to the invention may beused in the treatment of disorders caused by abnormal uteruscontraction, including dysmenorrhoea, missed abortion, hypertrophy andhyperkinesia.

Similarly, PTPase activity can also modulate the activity of tyrosinekinase and other enzymes associated with cell proliferation and celldifferentiation, as a result of which the compounds according to theinvention may also be used in the treatment and prophylaxis of fibromasof the uterus.

AT₂ -receptors play a part in the regulation of cardiac function. Thedemonstrated effect of AT₂ -receptors on T-type calcium flow may play animportant part in the heart in arrhythmogenesis and in the modulation ofpace-maker function in the sinoauricular node. Accordingly, thecompounds of the present invention may be used in the treatment ofcardiac insufficiency and arrhythmia. They are furthermore useful in thetreatment of cardiac hypertrophy, since AT₂ -receptors cause an increasein PTPase activity, which is generally to be regarded asgrowth-inhibiting.

AT₂ -receptors are furthermore found in the zona glomerulosa, zonafasciculata and medulla of the adrenal glands. Since T-type calciumflows are modulated and, furthermore, anti-proliferative properties areimparted by those receptors, the compounds according to the inventionmay be used in the treatment of hypertrophy and hypersecretion of theadrenal cortex, such as Cushing's syndrome, adrogenital syndrome andprimary hyperaldosteronism.

The modulation of T-type calcium flows enables the compounds accordingto the invention to be used in the treatment of disorders involved withthe deregulation of the pancreas and exocrinal secretion, such aspancreatitis, hyperinsulinism and Zollinger-Ellison syndrome.

There is a special need for medicaments to be available for thetreatment of post myocardial infarction in order effectively to treatcardiac failure following a cardiac infarction. An appropriate therapyshould advantageously be undertaken after the repairing and healingphase of the heart. An acute myocardial infarction is known to causeboth a change in haemodynamic effects and an alteration in structure inthe damaged and healthy zones of the heart. Thus, a myocardialinfarction reduces, for example, the maximum cardiac output and thestroke volume. Those haemodynamic effects can be ascertained in a mannerknown per se, for example in the rat model [Schoemaker et al.J.Mol.CellCardiol. 23, 187-197 (1991)]. Also associated with myocardialinfarction is a stimulation of the DNA synthesis occurring in theinterstice as well as an increase in the formation of collagen in theareas of the heart not affected [van Krimpen et al. J. Mol. CellCardiol.23, 1245-1253 (1991)].

Surprisingly, the compounds according to the invention and the saltsthereof reduce the DNA synthesis. Also, the post-myocardial treatmentcauses an improvement in the negative haemodynamic effects. Thoseregulatory effects are attributable to the binding of the compounds tothe AT₂ -receptor. These findings are obtained using the methodology,known per se, according to Schoemaker et al., J.Mol.CellCardiol. 23,187-197 (1991) and van Krimpen et al. J. Mol. CellCardiol. 23 1245-1253(1991) and also Smits et al., Journal of Cardiovascular Pharmacology,20:772-778 (1992). In both techniques, a cardiac infarction is inducedin rats in the rat model, and the active ingredient is administered overweeks after the infarction, for example using an osmotic minipump. Theactive ingredients are advantageously administered from three to fiveweeks after the myocardial infarction has been induced, and thehaemodynamic effects as well as the formation of the relevant DNA areascertained. The results clearly show that on the one hand the DNAsynthesis is significantly reduced and on the other hand the negativehaemodynamic effects are normalised. Corresponding animal experimentresults with the ACE-inhibitor captopril, known to be used in thetreatment of post myocardial infarction, could be confirmed withcaptopril also in humans [Pfeffer et al. N.Engl.J.Med. 1992, 327,669-677].

Altogether, the compounds according to the invention and the saltsthereof are therefore distinguished by a favourable profile of activity.

Accordingly, the compounds of formula I and the pharmaceuticallyacceptable salts thereof may be used, for example, as active ingredientsthat are employed, for example, in the treatment of disorders caused bymodulation of the AT₂ -receptor, for example in the treatment ofdisorders of the kind described hereinbefore. The invention thus relatesto the use of compounds of formula I and pharmaceutically acceptablesalts thereof in the preparation of corresponding medicaments and in thetherapeutic treatment of disorders caused by modulation of the AT₂-receptor. Also included in the preparation of the medicaments is thecommercial presentation of the active substances.

The compounds of formula I may be in the form of salts, especiallypharmaceutically acceptable salts. If the compounds I have, for example,at least one basic centre, they can form acid addition salts. Thosesalts are formed, for example, with strong inorganic acids, such asmineral acids, e.g. sulfuric acid, a phosphoric acid or a hydrohalicacid, with strong organic carboxylic acids, such as unsubstituted orsubstituted, e.g. halosubstituted, C₁ -C₄ alkanecarboxylic acids, e.g.acetic acid, saturated or unsaturated dicarboxylic acids, e.g. oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid,hydroxycarboxylic acids, e.g. ascorbic, glycolic, lactic, malic,tartaric or citric acid, amino acids, e.g. aspartic or glutamic acid, orbenzoic acid, or with organic sulfonic acids, such as unsubstituted orsubstituted, e.g. halosubstituted, C₁ -C₄ alkane- or aryl-sulfonicacids, e.g. methane- or p-toluene-sulfonic acid. Corresponding acidaddition salts may also be formed with a basic centre optionally presentin addition. Also, compounds I having at least one acid group (e.g. COOHor 5-tetrazolyl) can form salts with bases. Suitable salts with basesare, for example, metal salts, such as alkali metal or alkaline earthmetal salts, e.g. sodium, potassium or magnesium salts, or salts withammonia or an organic amine, such as morpholine, thiomorpholine,piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, e.g.ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- ordimethyl-propyl-amine, or a mono-, di- or tri-hydroxy-lower alkylamine,e.g. mono-, di- or tri-ethanolamine. Furthermore, corresponding internalsalts may be formed. Also included are salts that are not suitable forpharmaceutical use, which are used, for example, for the isolation orpurification of free compounds I or pharmaceutically acceptable saltsthereof.

The compounds according to the invention have at least two opticallyactive carbon atoms and may accordingly be in the form of stereoisomersor mixtures of stereoisomers or in the form of pure enantiomers ordiastereoisomers. The present invention also includes correspondingstereoisomers. Aryl and aryl, for example, in aryl-lower alkyl,aryl-lower alkoxy-lower alkyl, aryl-lower alkoxycarbonyl oraryloxycarbonyl and also in aryl-lower alkanoyl, is preferablycarbocyclic aryl, such as phenyl or naphthyl, or heterocyclic aryl, suchas monocyclic monoaza-, monooxa-, monothia-, diaza-, oxaza- orthiaza-aryl, e.g. pyrrolyl, pyridyl, furyl, thienyl, imidazolyl,isoxazolyl, or thiazolyl. Such carbocyclic and heterocyclic arylradicals are, for example, independently of one another, unsubstitutedor mono- or poly-substituted, e.g. di- or tri-substituted, bysubstituents selected from the group consisting of: lower alkyl,aryl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, loweralkoxy-lower alkoxy, aryl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino and aminothat is monosubstituted or disubstituted, the substituents beingindependent of one another, by lower alkyl, aryl-lower alkyl or by aryl,or disubstituted by lower alkylene or by lower alkyleneoxy-loweralkylene. Preferred aryl is phenyl that is unsubstituted or mono- orpoly-substituted, e.g. di- or tri-substituted, in the manner indicatedhereinbefore.

Acyl is, for example, lower alkanoyl, aryl-lower alkanoyl, or aroyl,especially benzoyl, that may be unsubstituted or may be substituted asindicated hereinbefore for carbocyclic aryl.

The general terms used hereinbefore and hereinafter have the followingmeanings, unless specified to the contrary:

The term "lower" denotes that corresponding groups and compounds eachcontain especially up to and including 7, preferably up to and including4, carbon atoms.

Lower alkyl ist especially C₁ -C₇ alkyl, that is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or acorresponding pentyl, hexyl or heptyl radical.

C₁ -C₄ alkyl is preferred.

Lower alkenyl is especially C₃ -C₇ alkenyl and is e.g. 2-propenyl or 1-,2- or 3-butenyl. C₃ -C₅ alkenyl is preferred.

Lower alkynyl is especially C₃ -C₇ alkynyl and is preferably propargyl.

Hydroxy-lower alkyl is especially hydroxy-C₁ -C₄ alkyl, such ashydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.

C₁ -C₂ alkylene is methylene or 1,1-ethylene or 1,2-ethylene.

C₃ -C₇ cycloalkyl is especially cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

C₃ -C₇ cycloalkyl-lower alkyl is especially C₃ -C₇ cycloalkyl-C₁ -C₇alkyl, such as cyclopropylmethyl, 2-cyclopropyl-ethyl,3-cyclopropyl-propyl, cyclopentyl-methyl, 2-cyclopentyl-ethyl,3-cyclopentyl-propyl, cyclohexylmethyl, 2-cyclohexyl-ethyl or3-cyclohexyl-propyl. C₅ -C₆ cycloalkyl-C₁ -C₄ alkyl, such ascyclohexylmethyl or 2-cyclohexyl-ethyl, is preferred.

Lower alkoxy is especially C₁ -C₇ alkoxy, that is methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy orcorresponding pentyloxy, hexyloxy or heptyloxy. C₁ -C₄ alkoxy ispreferred.

Lower alkoxy-lower alkyl is especially C₁ -C₄ alkoxy-C₁ -C₄ -alkyl, suchas 2-methoxyethyl, 2-ethoxyethyl, 2-(n-propyl)-ethyl or ethoxymethyl.

Lower alkoxy-lower alkoxy is especially C₁ -C₄ alkoxy-C₁ -C₄ -alkoxy,such as methoxymethoxy, ethoxymethoxy, 2-methoxy-ethoxy or2-ethoxy--ethoxy.

Halogen is especially halogen having an atomic number of up to andincluding 35, that is fluorine, chlorine or bromine and also includesiodine.

Lower alkylene is especially C₂ -C₇ alkylene, is straight-chain orbranched and is especially ethylene, 1,3-propylene, 1,4-butylene,1,2-propylene, 2-methyl-1,3-propylene or 2,2-dimethyl-1,3-propylene. C₂-C₅ alkylene is preferred.

Lower alkyleneoxy-lower alkylene is especially C₂ -C₄ alkylene-oxy-C₂-C₄ alkylene, preferably ethyleneoxyethylene.

Lower alkoxycarbonyl is especially C₂ -C₈ alkoxycarbonyl and is e.g.methoxy-, ethoxy-, propoxy- or pivaloyloxy-carbonyl. C₂ -C₅alkoxycarbonyl is preferred.

Lower alkoxy-lower alkoxycarbonyl is especially C₁ -C₄ alkoxy-C₁ -C₄alkoxycarbonyl, preferably ethoxy-ethoxycarbonyl, methoxyethoxycarbonylor isopropoxy-ethoxycarbonyl.

Naphthyl is especially 1- or 2-naphthyl.

Pyrrolyl is especially 2- or 3-pyrrolyl.

Pyridyl is especially 2-, 3- or 4-pyridyl.

Furyl is especially 2- or 3-furyl.

Thienyl is especially 2- or 3-thienyl.

Imidazolyl is especially 2-, 4- or 5-imidazolyl.

Isoxazolyl is especially 3- or 4-isoxazolyl.

Thiazolyl is especially 2-, 3- or 5-thiazolyl.

Lower alkanoyl is especially C₁ -C₇ alkanoyl and is e.g. formyl, acetyl,propionyl, butyryl, isobutyryl or pivaloyl. C₂ -C₅ alkanoyl ispreferred.

Phenyl-lower alkanoyl is especially phenyl-C₂ -C₅ alkanoyl and is e.g.phenylacetyl, 3-phenylpropionyl or 4-phenylbutyryl.

Lower alkylamino is especially C₁ -C₇ alkylamino and is e.g. methyl-,ethyl-, n-propyl- or isopropyl-amino. C₁ -C₄ alkylamino is preferred.

Phenyl-lower alkylamino is preferably phenyl-C₁ -C₄ alkylamino,especially benzyl- or 1- or 2-phenylethyl-amino.

Di-lower alkylamino is especially di-C₁ -C₄ alkylamino, such asdimethyl-, diethyl-, di(n-propyl)-, methyl-propyl-, methyl-ethyl-,methyl-butyl- or dibutyl-amino.

N-lower alkyl-N-phenyl-lower alkyl-amino is especially N-C₁ -C₄alkyl-N-phenyl-C₁ -C₄ alkyl-amino, preferably methyl-benzyl-amino orethyl-benzyl-amino.

Di(phenyl-lower alkyl)amino is especially di(phenyl-C₁ -C₄ alkyl)amino,preferably dibenzylamino.

Amino that is disubstituted by lower alkylene is especially C₂ -C₆alkyleneamino, preferably C₄ -C₆ alkyleneamino, such as 1-pyrrolidino or1-piperidino.

Amino that is disubstituted by lower alkyleneoxy-lower alkylene isespecially C₂ -C₄ alkyleneoxy-C₂ -C₄ alkyleneamino, preferably4-morpholino.

Halo-lower alkanesulfonyl is especially halo-C₁ -C₇ alkanesulfonyl, suchas chloromethane-, fluoro-dichloromethane-, trichloromethane- ortrifluoromethane-sulfonyl. Halo-C₁ -C₄ alkanesulfonyl is preferred.

The invention relates especially to compounds of formula I wherein

Ar is aryl;

X is --O-- or --S(O)_(n) -- and n is 0, 1 or 2;

X₁ is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, lower alkyl, aryl-lower alkyl or acyl;

R₂ is lower alkyl, aryl-lower alkyl or C₃ -C₇ cycloalkyl-lower alkyl;

R₃ is carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl,aryl-lower alkoxycarbonyl or aryloxycarbonyl;

the ring A and aromatic radicals are, independently of one another,unsubstituted or mono- or poly-substituted by substituents selected fromthe group consisting of: lower alkyl, aryl-lower alkyl, loweralkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, aryl-loweralkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl, nitro,halogen, trifluoromethyl, amino and amino that is monosubstituted ordisubstituted, the substituents being independent of one another, bylower alkyl, aryl-lower alkyl or by aryl, or disubstituted by loweralkylene or by lower alkyleneoxy-lower alkylene;

or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl;

X is --O-- or --S(O)_(n) -- and n is 0, 1 or 2;

X₁ is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, lower alkyl, lower alkyl that is substituted by phenyl,naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl orby thiazolyl, lower alkanoyl, lower alkanoyl that is substituted byphenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl,isoxazolyl or by thiazolyl, or benzoyl;

R₂ is (i) lower alkyl, lower alkyl that is substituted by phenyl,naphthyl, pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl orby thiazolyl, or C₃ -C₇ cycloalkyl-lower alkyl, or (ii) hydroxy-loweralkyl, lower alkoxy-lower alkyl, or lower alkoxy-lower alkyl in whichthe lower alkoxy moiety is substituted by phenyl, naphthyl, pyrrolyl,pyridyl furyl, thienyl, imidazolyl, isoxazolyl or by thiazolyl;

R₃ is (i) carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ or (ii) loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl phenyl-loweralkoxycarbonyl, benzoylcarbonyl, carbamoyl, lower alkylcarbamoyl,di-lower alkylcarbamoyl, phenyl-lower alkylcarbamoyl, diphenyl-loweralkylcarbamoyl, hydroxycarbamoyl, lower alkanesulfonyl-carbamoyl,halo-lower alkanesulfonyl or phenylsulfonyl;

the ring A and carbocyclic and heterocyclic aromatic radicals are,independently of one another, unsubstituted or mono- or poly-substitutedby substituents selected from the group consisting of: lower alkyl,lower alkyl that is substituted by phenyl, naphthyl, pyrrolyl, pyridyl,furyl, thienyl, imidazolyl, isoxazolyl or by thiazolyl, loweralkoxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl,nitro, halogen, trifluoromethyl, amino and amino that is monosubstitutedor disubstituted, the substituents being independent of one another, bylower alkyl, phenyl-lower alkyl or by phenyl, or disubstituted by loweralkylene or by lower alkyleneoxy-lower alkylene;

or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl;

X is --O-- or --S(O)_(n) -- and n is 0, 1 or 2;

X₁ is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl,phenyl-lower alkanoyl or benzoyl;

R₂ is lower alkyl, phenyl-lower alkyl or C₃ -C₇ cycloalkyl-lower alkyl;

R₃ is (i) carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ or (ii)carbamoyl or hydroxy-carbamoyl;

the ring A and carbocyclic and heterocyclic aromatic radical are,independently of one another, unsubstituted or mono- or poly-substitutedby substituents selected from the group consisting of: lower alkyl,phenyl-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy, loweralkoxy-lower alkoxy, phenyl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇cycloalkyl-lower alkyl, nitro, halogen, trifluoromethyl, amino and aminothat is monosubstituted or disubstituted, the substituents beingindependent of one another, by lower alkyl, phenyl-lower alkyl or byphenyl, or disubstituted by lower alkylene or by lower alkyleneoxy-loweralkylene;

or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl or phenyl substituted by C₁ -C₄ alkyl;

X is --O-- or --S(O)_(n) -- and n is 0, 1 or 2;

X₁ is C₁ -C₂ alkylene or a direct bond;

R₁ is hydrogen, C₁ -C₄ alkyl or C₂ -C₅ alkanoyl;

R₂ is phenyl-C₁ -C₄ alkyl wherein phenyl is unsubstituted or issubstituted by halogen, trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄alkoxy, or R₂ is C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl;

R₃ is carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ ;

the ring A is unsubstituted or mono- or poly-substituted by substituentsselected from the group consisting of:

C₁ -C₄ alkyl, halogen, C₁ -C₄ alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄alkoxy-C₁ -C₄ alkoxy, nitro, halogen and trifluoromethyl;

or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl substituted by C₁ -C₄ alkyl, lower alkoxy, halogen,trifluoromethyl, amino, lower alkylamino, di-lower alkylamino or bynitro;

X is --O--;

X₁ is methylene;

R₁ is hydrogen or C₂ -C₅ alkanoyl;

R₂ is phenyl-C₁ -C₄ alkyl wherein phenyl is unsubstituted or issubstituted by halogen, trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄alkoxy; or R₂ is C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl;

R₃ is carboxy, carbamoyl or hydroxycarbamoyl;

the ring A is unsubstituted or mono- or poly-substituted by substituentsselected from the group consisting of:

C₁ -C₄ alkyl, halogen, C₁ -C₄ alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄alkoxy-C₁ -C₄ alkoxy, nitro, halogen and trifluoromethyl;

or salts thereof.

The invention relates especially to compounds of formula I wherein

Ar is phenyl or phenyl substituted, especially in the para-position, byC₁ -C₄ alkyl, such as p-isopropylphenyl;

X is --O--;

X₁ is methylene;

R₁ is hydrogen or C₂ -C₅ alkanoyl;

R₂ is phenyl-C₁ -C₄ alkyl wherein phenyl is unsubstituted or issubstituted by halogen, trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄alkoxy; or R₂ is C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl;

R₃ is carboxy or 5-tetrazolyl;

the ring A is unsubstituted or is mono- or poly-substituted bysubstituents selected from the group consisting of:

C₁ -C₄ alkyl, halogen, C₁ -C₄ alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄alkoxy-C₁ -C₄ alkoxy, nitro, halogen and trifluoromethyl;

or salts thereof.

The invention relates especially to compounds of formula (Ia) ##STR3##wherein R₁ is hydrogen;

R₂ is phenyl-C₁ -C₄ alkyl, such as benzyl, wherein phenyl isunsubstituted or is substituted by halogen, such as fluorine,trifluoromethyl, C₁ -C₄ alkyl, such as methyl, or by C₁ -C₄ alkoxy, suchas methoxy, or R₂ is C₅ -C₆ cycloalkyl- C₁ -C₄ alkyl, such ascyclohexylmethyl or 2-cyclohexyl-ethyl;

R₃ is carboxy; and

R₄ is C₁ -C₄ alkyl, especially isopropyl, that is bonded especially inthe para-position;

or salts thereof.

The invention relates especially to compounds of formula (Ib) ##STR4##wherein R₁ is hydrogen;

R₂ is phenyl-C₁ -C₄ alkyl, such as benzyl, or C₅ -C₆ cycloalkyl-C₁ -C₄alkyl, such as cyclohexylmethyl or 2-cyclohexyl-ethyl;

R₃ is carboxy; and

R₄ is C₁ -C₄ alkyl, especially isopropyl;

or salts thereof.

The invention relates to compounds of formulae I, Ia and Ib wherein thecarbon atom having the variables R₂ and R₃ has the (S)-configuration.Preferred are compounds of formulae I, Ia and Ib wherein both the carbonatom having the variables R₂ and R₃, and the heterocycle carbon atom towhich the amino group is bonded, have the (S)-configuration.

The invention relates specifically to the novel compounds of formula Imentioned in the Examples and to the stereoisomers and salts thereof.

The invention relates furthermore to a process for the preparation ofcompounds of formula I and the stereoisomers and salts thereof, whichcomprises, for example,

a) in a compound of formula ##STR5## wherein Y₁ is a radical that can beconverted into the variable R₃, or in a salt thereof, converting Y₁ intothe variable R₃ ; or,

b) for the preparation of a compound of formula (I) wherein R₁ ishydrogen, or for the preparation of a salt thereof, in a compound offormula ##STR6## wherein Y₂ is an amino-protecting group, or in a saltthereof, removing the amino-protecting group; or

c) reacting a compound of formula ##STR7## with a compound of formula##STR8## (IVb), wherein Y₄ is a nucleofugal leaving group, or with acompound of formula R₂ --CO--R₃ (IVc) or a salt thereof; or

d) reacting a compound of formula ##STR9## with a compound of formula Y₆--X₁ --Ar (Vb), wherein Y₆ is a nucleofugal leaving group, or with asalt thereof; or

e) reacting a compound of formula ##STR10## wherein Y₇ is (i) oxo or(ii) reactive esterified hydroxy together with hydrogen, with a compoundof formula ##STR11## (VIb) or with a salt thereof; and in each case, ifdesired, isolating in free form or in salt form a compound of formula Iobtainable according to the process or in some other manner, convertinga compound of formula I obtainable according to the process or in someother manner into a different compound of formula I, separating amixture of isomers obtainable according to the process and isolating thedesired isomer and/or converting a free compound of formula I obtainableaccording to the process into a salt or converting a salt of a compoundof formula I obtainable according to the process into the free compoundof formula I or into a different salt.

The reactions described in the variants hereinbefore and hereinafter arecarried out in a manner known per se, e.g. in the absence or customarilyin the presence of a suitable solvent or diluent or a mixture thereof,if required with cooling, at room temperature or with heating, e.g. in atemperature range of approximately from -80° C. to the boilingtemperature of the reaction medium, preferably from approximately -10°to approximately +200° C., and, if necessary, in a closed vessel, underpressure, in an inert gas atmosphere and/or under anhydrous conditions.

Details concerning corresponding procedures and reaction conditions maybe found especially also in the Examples.

Variant a):

A radical Y₁ that can be converted into carboxy R₃ is, for example,functionally modified carboxy or a radical that can be convertedoxidatively into carboxy.

There comes into consideration as functionally modified carboxy, forexample, esterified carboxy different from R₃, amidated carboxy orcyano.

Esterified carboxy different from R₃ is, for example, carboxy esterifiedby an unsubstituted or substituted aliphatic, cycloaliphatic or aromaticalcohol. An aliphatic alcohol is, for example, a lower alkanol, such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol ortert-butanol, that is substituted by cyano or by a silyl radical, whilethere comes into consideration as a cycloaliphatic alcohol, for example,a 3- to 8-membered cycloalkanol, such as cyclo-pentanol, -hexanol or-heptanol. An aromatic alcohol is, for example, a phenol or aheterocyclic alcohol, each of which may be substituted, especiallyhydroxypyridine, e.g. 2-, 3- or 4-hydroxypyridine.

Amidated carboxy is, for example, carbamoyl, or carbamoyl that ismonosubstituted by hydroxy, amino or by unsubstituted or substitutedphenyl, mono- or di-substituted by lower alkyl, or disubstituted by 4-to 7-membered alkylene or by 3-aza-, 3-lower alkylaza-, 3-oxa- or3-thia-alkylene. There may be mentioned as examples carbamoyl, N-mono-or N,N-di-lower alkylcarbamoyl, such as N-methyl-, N-ethyl-,N,N-di-methyl-, N,N-diethyl- and N,N-dipropyl-carbamoyl, pyrrolidino-and piperidino-carbonyl, morpholino-, piperazino-, 4-methylpiperazino-and thiomorpholino-carbonyl, anilinocarbonyl and anilinocarbonylsubstituted by lower alkyl, lower alkoxy and/or by halogen.

Preferred functionally modified carboxy is, for example, cyano-loweralkoxycarbonyl, such as 2-cyanoethoxycarbonyl, silyloxy-carbonyl, suchas tri-lower alkylsilyloxycarbonyl, e.g. tri(m)ethylsilyloxycarbonyl,and cyano.

Preferred Y₁ is, for example, cyano.

Compounds of formula I wherein R₃ is carboxy may be prepared, forexample, starting from compounds of formula II wherein Y₁ is cyano,esterified carboxy different from R₃, or amidated carboxy, by means ofhydrolysis, especially in the presence of a base.

The following Y₁ especially can be converted in a manner known per seinto carboxy R₃ : 2-cyanoethoxycarbonyl Y₁ can be converted into carboxyR₃, for example, by means of hydrolysis in the presence of a base,2-trimethylsilyloxycarbonyl can be converted into carboxy R₃ bytreatment with a fluoride, such as an alkali metal fluoride, e.g. sodiumfluoride, and silyloxycarbonyl Y₁ can be converted into carboxy R₃ bytreatment with an acid.

There come into consideration as bases, for example, alkali metalhydroxides, hydrides, amides, alkanolates, carbonates,triphenylmethylides, di-lower alkylamides, aminoalkylamides or loweralkylsilylamides, naphthaleneamines, lower alkylamines, basicheterocycles, ammonium hydroxides, as well as carbocyclic amines. Theremay be mentioned by way of example sodium hydroxide, hydride and amide,potassium tert-butanolate, potassium carbonate, lithiumtriphenylmethylide, lithium diisopropylamide, potassium3-(aminopropyl)-amide, potassium bis-(trimethylsilyl)-amide,dimethylaminonaphthalene, di- or tri-ethylamine, orethyl-diisopropylamine, N-methylpiperidine, pyridine,benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) and also 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

There comes into consideration as an acid, for example, a stronginorganic acid, such as a mineral acid, e.g. sulfuric acid, a phosphoricacid or a hydrohalic acid, a strong organic carboxylic acid, such as anunsubstituted or substituted, e.g. halosubstituted, C₁ -C₄alkanecarboxylic acid, e.g. acetic or trifluoroacetic acid, or anorganic sulfonic acid, such as an unsubstituted or substituted, e.g.halosubstituted, C₁ -C₄ alkane- or aryl-sulfonic acid, e.g. methane- orp-toluene-sulfonic acid.

There comes into consideration as a radical that can be convertedoxidatively into carboxy, for example, hydroxymethyl, or formyloptionally formed in situ.

Starting from compounds of formula II wherein Y₁ is hydroxymethyl orformyl, carboxy R₃ can be produced by means of oxidation. The oxidationis carried out, for example, in an inert solvent, such as in a loweralkanecarboxylic acid, e.g. acetic acid, a ketone, e.g. acetone, anether, e.g. tetrahydrofuran, a heterocyclic aromatic compound, e.g.pyridine, or in water, or in a mixture thereof, if necessary withcooling or heating, e.g. in a temperature range of from approximately 0°to approximately +150° C. There come into consideration as oxidizingagents, for example, oxidizing transition metal compounds, especiallythose with elements of sub-group I, VI or VII. There may be mentioned asexamples: silver compounds, such as silver nitrate, oxide andpicolinate, chromium compounds, such as chromium trioxide and potassiumdichromate, and manganese compounds, such as potassium,tetrabutylammonium and benzyltriethylammonium permanganate. Otheroxidizing agents are, for example, suitable compounds with elements ofmain group IV, such as lead dioxide, or halogen/oxygen compounds, suchas sodium iodate or potassium periodate.

A radical Y₁ that can be converted into 5-tetrazolyl R₃ is, for example,cyano or N-protected 5-tetrazolyl.

In order to prepare compounds of formula I wherein R₃ is 5-tetrazolyl,there is used as starting material, for example, a compound of formulaII wherein Y₁ is cyano, which is reacted with an azide, for example withHN₃ or especially a salt, such as an alkali metal salt, thereof, or withan organotin azide, such as a tri-lower alkyltin or triaryltin azide.Preferred azides are, for example, sodium and potassium azide and alsotri-C₁ -C₄ alkyl-, e.g. triethyl- or tributyl-tin azide, andtriphenyltin azide.

There come into consideration as protecting groups of N-protected5-tetrazolyl R₃ the protecting groups customarily used in tetrazolechemistry, especially triphenylmethyl, unsubstituted or substituted,e.g. nitro-substituted, benzyl, such as 4-nitrobenzyl, loweralkoxymethyl, such as methoxy- or ethoxy-methyl, lower alkylthiomethyl,such as methylthiomethyl, and 2-cyanoethyl, also lower alkoxy-loweralkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl, and alsophenacyl. The removal of the protecting groups is carried out inaccordance with known methods, for example as described in J. Green,Protective Groups in Organic Synthesis, Wiley-Interscience (1980). Forexample triphenylmethyl is customarily removed by hydrolysis, especiallyin the presence of an acid, or by hydrogenolysis in the presence of ahydrogenation catalyst, 4-nitrobenzyl is removed, for example, byhydrogenolysis in the presence of a hydrogenation catalyst, methoxy- orethoxy-methyl is removed, for example, by treatment with a tri-loweralkyltin bromide, such as triethyl- or tributyl-tin bromide,methylthiomethyl is removed, for example, by treatment withtrifluoroacetic acid, 2-cyanoethyl is removed, for example, byhydrolysis, for example with sodium hydroxide solution,2-methoxyethoxymethyl is removed, for example, by hydrolysis, e.g. withhydrochloric acid, and benzyloxymethyl and phenacyl are removed, forexample, by hydrogenolysis in the presence of a hydrogenation catalyst.

A radical Y₁ that can be converted into PO₂ H₂ or PO₃ H₂ R₃ is, forexample, a functional derivative of PO₂ H₂ or PO₃ H₂ respectively.

A corresponding radical Y₁ that can be converted into R₃ is, forexample, a group --N₂ ⁺ A⁻, wherein A⁻ is an anion of an acid, such as amineral acid. Corresponding diazonium compounds are, for example,reacted in a manner known per se with a P(III) halide, such as PCl₃ orPBr₃, and worked up hydrolytically, compounds of formula I wherein R₃ isPO₃ H₂ being obtainable.

A radical Y₁ that can be converted into SO₃ H R₃ is, for example, themercapto group. Starting compounds of formula II containing such a groupare oxidized, for example by oxidation processes known per se, tocompounds of formula I wherein R₃ is SO₃ H. There come intoconsideration as oxidizing agents, for example, inorganic peracids, suchas peracids of mineral acids, e.g. periodic acid or persulfuric acid,organic peracids, such as percarboxylic or persulfonic acids, e.g.performic, peracetic, trifluoroperacetic or perbenzoic acid orp-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids,e.g. mixtures of hydrogen peroxide and acetic acid. Frequently theoxidation is carried out in the presence of suitable catalysts. Theremay be mentioned as catalysts suitable acids, such as unsubstituted orsubstituted carboxylic acids, e.g. acetic acid or trifluoroacetic acid,and transition metal oxides, such as oxides of elements of sub-group VI,e.g. molybdenum oxide or tungsten oxide. The oxidation is carried outunder mild conditions, e.g. at temperatures of from approximately -50°to approximately +100° C.

The starting material of formula II is obtainable, for example, byreacting a compound of formula ##STR12## or a salt thereof, wherein Y₃is one of the above-mentioned amino-protecting groups, for examplephthaloyl, with a compound of formula

    Ar--X.sub.1 --Y.sub.4                                      (IIb)

wherein Y₄ is reactive esterified hydroxy and X₁ is C₁ -C₂ alkylene, inthe presence of a base. In the next reaction step, the amino-protectinggroup is removed in a manner known per se, for example the phthaloylgroup is removed by treatment with hydrazine hydrate. A compound offormula ##STR13## so obtainable is then reacted with a compound offormula ##STR14## wherein Y₄ is a nucleofugal leaving group, such as adiazonium radical or reactive esterified hydroxy, in the presence ofbase, to form a compound of formula II wherein R₁ is hydrogen. Ifdesired a corresponding compound may be N-alkylated or N-acylated in amanner known per se to form a compound of formula II.

Reactive esterified hydroxy is especially hydroxy esterified by a stronginorganic acid or organic sulfonic acid, for example halogen, such aschlorine, bromine or iodine, or sulfonyloxy, such as hydroxysulfonyloxy,halosulfonyloxy, e.g. fluorosulfonyloxy, unsubstituted or substituted,e.g. halosubstituted, C₁ -C₇ alkanesulfonyloxy, e.g. methane- ortrifluoromethane-sulfonyloxy, C₅ -C₇ cycloalkanesulfonyloxy, e.g.cyclohexanesulfonyloxy, or unsubstituted or substituted, e.g. C₁ -C₇alkyl- or halo-substituted, benzenesulfonyloxy, e.g. p-bromophenyl- orp-toluene-sulfonyloxy, especially halogen, such as chloride, bromide oriodide, as well as sulfonyloxy, such as methane- orp-toluene-sulfonyloxy.

A specific method of preparing compounds of formula II is describedespecially in working Example 1.

The starting materials of formulae IIa, IIb and IId are known or can beprepared according to methods known per se.

Variant b):

There come into consideration as the amino-protecting group Y₂ theprotecting groups customarily used in peptide chemistry, especiallytriphenylmethyl, unsubstituted or substituted, e.g. nitro-substituted,benzyl, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- orethoxymethyl, lower alkylthiomethyl, such as methylthiomethyl, and2-cyanoethyl, also lower alkoxy-lower alkoxymethyl, such as2-methoxyethoxymethyl, benzyloxymethyl and also phenacyl. The removal ofthe protecting groups is carried out in accordance with known methods,for example as described in J. Green, Protective Groups in OrganicSynthesis, Wiley-Interscience (1980). For example triphenylmethyl iscustomarily removed by hydrolysis, especially in the presence of anacid, or by hydrogenolysis in the presence of a hydrogenation catalyst,4-nitrobenzyl is removed, for example, by hydrogenolysis in the presenceof a hydrogenation catalyst, methoxy- or ethoxy-methyl is removed, forexample, by treatment with a tri-lower alkyltin bromide, such astriethyl- or tributyl-tin bromide, methylthiomethyl is removed, forexample, by treatment with trifluoroactic acid, 2-cyanoethyl is removed,for example, by hydrolysis, for example with sodium hydroxide solution,2-methoxyethoxymethyl is removed, for example, by hydrolysis, e.g. withhydrochloric acid, and benzyloxymethyl and phenacyl are removed, forexample, by hydrogenolysis in the presence of a hydrogenation catalyst.

The starting material of formula III is obtainable, for example, byreacting one of the compounds described hereinbefore of formula##STR15## with a compound of formula ##STR16## wherein Y₄ is anucleofugal leaving group, such as a diazonium radical or reactiveesterified hydroxy, in the presence of a base to form a compound offormula II wherein R₁ is hydrogen, and then introducing theamino-protecting group in a manner known per se.

Variant c):

A nucleofugal leaving group Y₄ is, for example, a diazonium radical oris reactive esterified hydroxy as defined hereinbefore. Y₄ isadvantageously halogen, such as chlorine or bromine, or sulfonyloxy,such as methanesulfonyloxy or 4-nitrophenylsulfonyloxy.

The reaction is carried out in a manner known per se, advantageously inthe presence of one of the bases specified hereinbefore.

Some of the starting materials are known, or they can be preparedaccording to methods known per se.

The preparation of the starting material of formula IVa is carried out,for example, as described in connection with the preparation ofcompounds of formula III in Variant b).

Variant d):

There comes into consideration as the nucleofugal leaving group Y₆especially reactive esterified hydroxy, which, for example, is asdefined hereinbefore.

The reaction is carried out in a manner known per se, advantageously inthe presence of one of the bases specified hereinbefore.

The reaction is advantageously carried out with compounds of formula Vawherein R₃ is other than carboxy. The reaction is especiallyadvantageously carried out with compounds of formula Va wherein inaddition R₁ is other than hydrogen.

Some of the starting materials are known, or they can be preparedaccording to methods known per se.

To prepare a compound of formula (Va), for example a compound of formulaIIc is used as starting material and is reacted analogously to Variantc) with a compound of formula IVb or IVc, advantageously in the presenceof one of the bases defined hereinbefore.

Variant e):

The reaction is carried out in a manner known per se.

The reductive alkylation (Y₇ =oxo) is carried out in the presence ofcustomary reducing agents, whereas the substitutive N-alkylation (Y₇=reactive esterified hydroxy together with hydrogen) is carried outpreferably in the presence of one of the bases defined hereinbefore.

Some of the starting materials are known, or they can be preparedaccording to methods known per se.

Some of the starting materials used in the above process variants, andthe preparation of such materials, are described in U.S. Pat. No.4,477,464.

A compound of formula I obtainable according to the process or in someother manner may be converted in a manner known per se into a differentcompound of formula I.

If one of the variables contains amino, corresponding compounds I may beN-(ar)alkylated in a manner known per se; similarly, carbamoyl orradicals containing carbamoyl may be N-(ar)alkylated. The (ar)alkylationis carried out, e.g., with an (aryl-)C₁ -C₇ alkyl halide, e.g. bromideor iodide, an (aryl-)C₁ -C₇ alkanesulfonate, e.g. methanesulfonate orp-toluenesulfonate, or a di-C₁ -C₇ alkyl sulfate, e.g. dimethyl sulfate,preferably under basic conditions, such as in the presence of sodiumhydroxide solution or potassium hydroxide solution, and advantageouslyin the presence of a phase transfer catalyst, such as tetrabutylammoniumbromide or benzyltrimethylammonium chloride, in which case, however,more strongly basic condensation agents, such as alkali metal amides,hydrides or alcoholates, e.g. sodium amide, sodium hydride or sodiumethanolate, may be necessary.

A compound of formula I wherein R₁ is hydrogen may be acylated in amanner known per se to a compound of formula I wherein R₁ is acyl. Thereaction is carried out, for example, with a compound of formula R₁ --OHor a reactive derivative thereof. Reactive derivatives of compounds offormula R₁ --OH are, for example, reactive anhydrides derived therefrom.

Anhydrides of acids of formula R₁ --OH may be symmetric or preferablymixed anhydrides of those acids, for example anhydrides with inorganicacids, such as acid halides, especially acid chlorides (obtainable, forexample, by treatment of the corresponding acid with thionyl chloride,phosphorus pentachloride or oxalyl chloride; acid chloride method),azides (obtainable, for example, from a corresponding acid ester via thecorresponding hydrazide by treatment thereof with nitrous acid; azidemethod), anhydrides with carbonic acid semiesters, for example carbonicacid lower alkyl semiesters (obtainable, for example, by treatment ofthe corresponding acid with chloroformic acid lower alkyl esters or witha 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, e.g.1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixed O-alkylcarbonicacid anhydrides method), anhydrides with dihalogenated, especiallydichlorinated, phosphoric acid (obtainable, for example, by treatment ofthe corresponding acid with phosphorus oxychloride; phosphorusoxychloride method), anhydrides with other phosphoric acid derivatives(for example those obtainable withphenyl-N-phenylphosphoramidochloridate) or with phosphorous acidderivatives, or anhydrides with organic acids, such as mixed anhydrideswith organic carboxylic acids (obtainable, for example, by treatment ofthe corresponding acid with an unsubstituted or substituted loweralkane- or phenyl-lower alkane-carboxylic acid halide, for examplephenylacetic acid chloride, pivalic acid chloride or trifluoroaceticacid chloride; mixed carboxylic acid anhydrides method) or with organicsulfonic acids (obtainable, for example, by treatment of a salt, such asan alkali metal salt, of the corresponding acid with a suitable organicsulfonic acid halide, such as a lower alkane- or aryl-, for examplemethane- or p-toluene-sulfonic acid chloride; mixed sulfonic acidanhydrides method), as well as symmetric anhydrides (obtainable, forexample, by condensation of the corresponding acid in the presence of acarbodiimide or 1-diethylaminopropyne; symmetric anhydrides method).

Condensation to form an amide bond may be carried out in a manner knownpew se, for example as described in standard works, such as Houben-Weyl,"Methoden der organischen Chemie", 4th edition, Volume 15/II, GeorgThieme Verlag, Stuttgart 1974, "The Peptides" (editors E. Gross and J.Meienhofer), Volumes 1 and 2, Academic Press, London and New York,1979/1980, or M. Bodanszky, "Principles of Peptide Synthesis",Springer-Verlag, Berlin 1984.

The condensation may be carried out in the presence of one of thecustomary condensation agents. Customary condensation agents are, forexample, carbodiimides, for example diethyl-, dipropyl-,N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide or especiallydicyclohexylcarbodiimide, also suitable carbonyl compounds, for examplecarbonyldiimidazole, 1,2-oxazolium compounds, for example2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate and2-tert-butyl-5-methylisoxazolium perchlorate or a suitable acylaminocompound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,and also activated phosphoric acid derivatives, for examplediphenylphosphoryl azide, diethylphosphoryl cyanide,phenyl-N-phenylphosphoramidochloridate,bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride or1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate.

If desired an organic base is added, for example a tri-lower alkylaminehaving bulky radicals, such as ethyldiisopropylamine, or a heterocyclicbase, for example pyridine, 4-dimethylaminopyridine or preferablyN-methylmorpholine.

The condensation of acid anhydrides with amines may be effected, forexample, in the presence of inorganic carbonates, for example alkalimetal carbonates or hydrogen carbonates, such as sodium or potassiumcarbonate or hydrogen carbonate (usually together with a sulfate).

The condensation is carried out preferably in an inert, polar, aprotic,preferably anhydrous solvent or solvent mixture, for example in acarboxylic acid amide, for example formamide or dimethylformamide, ahalogenated hydrocarbon, for example methylene chloride, carbontetrachloride or chlorobenzene, a ketone, for example acetone, a cyclicether, for example tetrahydrofuran, an ester, for example ethyl acetate,or a nitrile, for example acetonitrile, or in a mixture thereof, asappropriate at reduced or elevated temperature, for example in atemperature range of from approximately -40° C. to approximately +100°C., preferably from approximately -10° C. to approximately +50° C., and,where appropriate, under an inert gas atmosphere, for example a nitrogenatmosphere.

Reactive acid derivatives may also be formed in situ.

In compounds of formula I that contain an esterified carboxy group assubstituent, such a group may be converted into a free carboxy group,for example by means of hydrolysis, for example in the presence of abasic agent or an acid agent, such as a mineral acid.Tert-butoxycarbonyl, for example, may furthermore be converted intocarboxy, for example in a manner known per se, such as by treatment withtrihaloacetic acid, such as trifluoroacetic acid, advantageously underanhydrous conditions, and benzyloxycarbonyl may be converted intocarboxy, for example, by catalytic hydrogenation in the presence of ahydrogenation catalyst, for example in the manner described below.

In addition, in compounds of formula I that have a carboxy group assubstituent (especially if R₃ is other than carboxy), the carboxy groupmay be converted, for example by treatment with an alcohol, such as alower alkanol, in the presence of a suitable esterifying agent, such asan acid reagent, e.g. an inorganic or organic acid or a Lewis acid, e.g.zinc chloride, or a water-binding condensation agent, e.g. acarbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by treatmentwith a diazo reagent, such as a diazo-lower alkane, e.g. diazomethane,into a correspondingly esterified carboxy group. The latter may also beobtained by treating compounds of formula I wherein the carboxy group isin free form or in the form of a salt, such as an ammonium or metalsalt, e.g. an alkali metal salt, such as a sodium or potassium salt,with a C₁ -C₇ alkyl halide, e.g. methyl or ethyl bromide or iodide, orwith an organic sulfonic acid ester, such as a corresponding C₁ -C₇alkyl ester, e.g. methanesulfonic acid or p-toluenesulfonic acid methylester or ethyl ester.

Compounds of formula I that contain an esterified carboxy group assubstituent may be converted into different ester compounds of formula Iby transesterification, e.g. by treatment with an alcohol, customarilywith an alcohol higher than that corresponding to the esterified carboxygroup in the starting material, in the presence of a suitabletransesterification agent, such as a basic agent, e.g. an alkali metalC₁ -C₇ alkanoate, C₁ -C₇ alkanolate or cyanide, such as sodium acetate,methanolate, ethanolate, tert-butanolate or cyanide, or of a suitableacid agent, where necessary with removal of the alcohol formed, e.g. bydistillation. It is also possible to use as starting material acorresponding so-called activated ester of formula I that contains anactivated esterified carboxy group as substituent (see below) andconvert that into a different ester by treatment with a C₁ -C₇ alkanol.

In compounds of formula I that contain a carboxy group as substituent,this may also first of all be converted into a reactive derivative, suchas an anhydride (also a mixed anhydride), an acid halide, e.g. an acidchloride (e.g. by treatment with a thionyl halide, e.g. thionylchloride), an anhydride with a formic acid ester, e.g. a formic acid C₁-C₇ alkyl ester (e.g. by treatment of a salt, such as an ammonium oralkali metal salt, with a haloformic, such as a chloroformic, acidester, such as a C₁ -C₇ alkyl ester), or an activated ester, such as acyanomethyl, nitrophenyl, e.g. 4-nitrophenyl, or polyhalophenyl, e.g.pentachlorophenyl, ester (e.g. by treatment with a corresponding hydroxycompound in the presence of a suitable condensation agent, such asN,N'-dicyclohexylcarbodiimide), and such a reactive derivative may thenbe reacted with a corresponding alcohol component so as to obtaincorresponding ester compounds of formula I. Those may be obtaineddirectly or by way of intermediate compounds; for example an activatedester, such as a 4-nitrophenyl ester, of a compound of formula Icontaining a carboxy group may first of all be reacted with a1-unsubstituted imidazole and the resulting 1-imidazolylcarbonylcompound may be reacted with a corresponding ester component.

If an aromatic ring contains a hydrogen atom as substituent, then thatmay be replaced by a halogen atom in customary manner using ahalogenating agent, e.g. by bromine using bromine, hypobromic acid, anacylhypobromite or another organic bromine compound, e.g.N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridiniumperbromide, dioxane dibromide, 1,3-dibromo-5,5-dimethylhydantoin or2,4,4,6-tetrabromo-2,5-cyclohexanedien-1-one, or by chlorine usingelemental chlorine, e.g. in a halogenated hydrocarbon, such aschloroform, and with cooling, e.g. to approximately -10° C.

If an aromatic ring contains an amino group, then that may be diazotisedin customary manner, e.g. by treatment with a nitrite, e.g. sodiumnitrite, in the presence of a suitable protonic acid, e.g. a mineralacid, the reaction temperature advantageously being maintained belowapproximately 5° C. The diazonium group so obtainable, which is in saltform, may be substituted according to conventional processes, forexample as follows: by a hydroxy group analogously to decomposition tophenol in the presence of water; by an alkoxy group by treatment with acorresponding alcohol, for which energy must be supplied; by thefluorine atom analogously to the Schiemann reaction in the thermolysisof corresponding diazonium tetrafluoroborates; or by chlorine, bromine,iodine or the cyano group analogously to the Sandmeyer reaction byreaction with corresponding Cu(I) salts, initially with cooling, e.g. tobelow approximately 5° C., and then with heating, e.g. to fromapproximately 60° to approximately 150° C.

The invention relates especially to the processes described in theExamples.

Salts of compounds of formula I may be prepared in a manner known perse. For example acid addition salts of compounds of formula I areobtained by treatment with a suitable acid or a suitable ion exchangereagent. Salts of compounds I may be converted into free compounds I incustomary manner, and acid addition salts may be converted into freecompounds I e.g. by treatment with a suitable basic agent or a suitableion exchange reagent.

Salts of compounds I may be converted into different salts of compoundsI in a manner known per se.

Depending on the reaction procedure and reaction conditions, compounds Ihaving salt-forming, especially basic, properties, may be obtained infree form or in the form of salts.

Owing to the close relationship between the compounds I in free form andin the form of their salts, hereinbefore and hereinafter any referenceto the free compound I and its salts should be understood as includingalso the corresponding salts and the free compound I, respectively,where appropriate and expedient.

The compounds I, including the salts of salt-forming compounds, may alsobe obtained in the form of their hydrates and/or may include othersolvents, e.g. solvents used for crystallisation.

Depending on the choice of starting materials and procedures, thecompounds I and their salts may be in the form of one of the possibleisomers or a mixture thereof, for example depending on the number andthe absolute and relative configuration of the asymmetric carbon atomsthey may be in the form of pure isomers, such as antipodes and/ordiastereoisomers, or in the form of mixtures of isomers, such asmixtures of enantiomers, e.g. racemates, mixtures of diastereoisomers ormixtures of racemates.

Resulting mixtures of diastereoisomers and mixtures of racemates can beseparated in known manner into the pure diastereoisomers or racemates onthe basis of the physico-chemical differences between the constituents,for example by fractional crystallisation. Resulting mixtures ofenantiomers, such as racemates, may be resolved into the opticalantipodes according to known methods, for example by recrystallisationfrom an optically active solvent, chromatography using chiraladsorbents, by means of suitable microorganisms, by cleavage withspecific immobilised enzymes, by the formation of inclusion compounds,e.g. using chiral crown ethers, only one enantiomer being complexed, orby conversion into diastereoisomeric salts, for example by reaction of abasic end-product racemate with an optically active acid, such as acarboxylic acid, for example tartaric acid or malic acid, or sulfonicacid, e.g. camphorsulfonic acid, and separation of the mixture ofdiastereoisomers obtained in that manner, for example on the basis oftheir different solubilities, into the diastereoisomers, from which thedesired enantiomer can be freed by the action of suitable agents.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining steps are carried out, or inwhich a starting material is used in the form of a derivative or saltand/or its racemates or antipodes or, especially, is formed under thereaction conditions.

The starting materials and intermediates used in the process of thepresent invention are preferably those which lead to the compounds Idescribed at the beginning as being especially valuable. The inventionextends also to novel starting materials and intermediates for thepreparation of compounds I, to the use thereof and to a process for thepreparation thereof, the variables A, X, X₁, R₁, R₂, R₃ and R₄ havingthe meanings given for the compounds I.

The compounds of formula I and the pharmaceutically acceptable saltsthereof may be used, preferably in the form of pharmaceuticallyacceptable compositions, in a method for the prophylactic and/ortherapeutic treatment of the animal or human body, especially for thetreatment of disorders that are brought about by stimulation or blockingof the AT₂ -receptor.

The invention therefore also relates to pharmaceutical compositions thatcomprise as active ingredient a compound I in free form or in the formof a pharmaceutically acceptable salt as well as to a process for thepreparation thereof. The pharmaceutical compositions are for enteral,such as oral, or also rectal or parenteral administration towarm-blooded animals, and comprise the pharmacological active ingredienton its own or together with customary pharmaceutical excipients. Thepharmaceutical compositions contain e.g. approximately from 0.1% to100%, preferably from approximately 1% to approximately 60%, activeingredient. Pharmaceutical compositions for enteral and parenteraladministration are e.g. in unit dose forms, such as dragees, tablets,capsules or suppositories, and also ampoules. They are prepared in amanner known per se, e.g. by means of conventional mixing, granulating,confectioning, dissolving or lyophilising processes. For example,pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture, and processing the mixture or granules,if desired or necessary after the addition of appropriate excipients, toform tablets or dragee cores.

Suitable carriers are especially fillers, such as sugars, e.g. lactose,saccharose, mannitol or sorbitol, cellulose preparations and/or calciumphosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, andbinders, such as starch pastes, using e.g. corn, wheat, rice or potatostarch, gelatin, gum tragacanth, methylcellulose and/orpolyvinylpyrrolidone, and, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, cross-linkedpolyvinylpyrrolidone, agar or alginic acid or a salt thereof, such assodium alginate. Excipients are especially flow conditioners andlubricants, e.g. silicic acid, talc, stearic acid or salts thereof, suchas magnesium or calcium stearate, and/or polyethylene glycol. Drageecores are provided with suitable, optionally enteric, coatings, therebeing used, inter alia, concentrated sugar solutions which may comprisegum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/ortitanium dioxide, or coating solutions in suitable organic solvents orsolvent mixtures, or, for the preparation of enteric coatings, solutionsof suitable cellulose preparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Dyes or pigments may be added tothe tablets or dragee coatings, e.g. for identification purposes or toindicate different doses of active ingredient.

Other orally administrable pharmaceutical compositions are dry-filledcapsules consisting of gelatin, and also soft sealed capsules consistingof gelatin and a plasticiser, such as glycerol or sorbitol. Thedry-filled capsules may contain the active ingredient in the form ofgranules, for example in admixture with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and, if desired, stabilisers. In soft capsules, the activeingredient is preferably dissolved or suspended in suitable liquids,such as fatty oils, paraffin oil or liquid polyethylene glycols, towhich stabilisers may also be added.

There come into consideration as rectally administrable pharmaceuticalcompositions e.g. suppositories that consist of a combination of theactive ingredient with a suppository base. Suitable suppository basesare e.g. natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols and higher alkanols. It is also possible to usegelatin rectal capsules, which contain a combination of the activeingredient with a base material. There come into consideration as basematerials e.g. liquid triglycerides, polyethylene glycols and paraffinhydrocarbons.

There are suitable for parenteral administration especially aqueoussolutions of an active ingredient in water-soluble form, e.g. in theform of a water-soluble salt, or also suspensions of the activeingredient, such as corresponding oily injection suspensions, therebeing used suitable lipophilic solvents or vehicles, such as fatty oils,e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate ortriglycerides, or aqueous injection suspensions that compriseviscosity-increasing substances, e.g. sodium carboxymethyl-cellulose,sorbitol and/or dextran, and, if desired, also stabilisers.

The dosage of the active ingredient may depend on various factors, suchas mode of administration, species of warm-blooded animal, age and/orindividual condition. For a patient weighing approximately 75 kg, theestimated approximate daily dose in the case of oral administration isnormally from approximately 10 mg to approximately 2250 mg, especiallyfrom approximately 10 mg to approximately 250 mg.

The following Examples illustrate the invention described above; theyare not, however, intended to limit the scope thereof in any way.Temperatures are quoted in degrees Celsius (° C).

EXAMPLE 1

3-(S)-[(1-(S)-Carboxy-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine

1.5 g of3-(S)-[(S)-1-ethoxycarbonyl-3-cyclohexyl-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepineare dissolved in 36 ml of methanol, 5 ml of 2N aqueous sodium hydroxidesolution are added and the mixture is stirred for 6 hours at roomtemperature. The reaction mixture is acidified with 1N hydrochloric acidand extracted twice with ethyl acetate and the organic phases are washedtwice with water. The combined ethyl acetate phases are dried oversodium sulfate and concentrated by evaporation. The residue is taken upin a small amount of ether and crystallises spontaneously. The materialis filtered off and dried overnight at 80° C. under a high vacuum. M.p.120°-122° C. ##STR17##

The starting material may be prepared, for example, as follows:

a)(S)-3-(tert-Butoxycarbonylamino)-5-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one44 g of(S)-3-(tert-butoxycarbonylamino)-2,3-dihydro-1,5(5H)-benzoxazepin-4-one(Chem. Pharm. Bull. 34, 1128 (1986)) are dissolved in 450 ml of absolutedimethylformamide, 44 g of potassium carbonate are added and the batchis stirred at room temperature for 2.5 hours. The first third (of atotal of 32 g) of p-isopropylbenzyl chloride and 1.4 g of potassiumiodide are added thereto and the batch is stirred at room temperaturefor 15 hours. The second third of p-isopropylbenzyl chloride is addedand, after a further 24 hours, the last third is added, whereupon thebatch is stirred again for 48 hours. The reaction mixture isconcentrated under a high vacuum, taken up in ethyl acetate, washed withwater, with dilute hydrochloric acid and again with water, and driedover sodium sulfate. Flash chromatography (900 g of silica gel, eluantpetroleum ether/ethyl acetate 4:1) yields the product in the form of aresin. R_(f) value (eluant hexane/ethyl acetate 1:4): 0.33.

b)(S)-3-Amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride

55 g of(S)-3-(tert-butoxycarbonylamino)-5-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-oneare dissolved in 180 ml of approximately 5 hydrochloric acid in ethylacetate, foaming occurring. After stirring for two hours, theochre-coloured suspension is concentrated and recrystallised from ether.The hygroscopic product has a m.p. of 215° C. (decomp.).

c)3-(S)-[(1-(S)Ethoxycarbonyl-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine

1.5 g of(S)-3-amino-4-oxo-5-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride, 2.93 g of(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethylester (Helv. Chim. Acta 71 (2), 337, 1988), 1.85 ml ofN-methylmorpholine and 2 ml of dimethylformamide are heated at 75° C.for 3 days. The reaction mixture is concentrated and separated by meansof flash chromatography (230 g of silica gel, eluant hexane/ethylacetate 4:1). The product is obtained in the form of a colourless resin.R_(f) value (eluant hexane/ethyl acetate 4:1): 0.36.

EXAMPLE 2

3-(R)-[(1-(S)-Carboxy-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine

Obtained analogously to Example 1,starting from 1.3 g of3-(R)-[(1-(S)-ethoxycarbonyl-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine.Crystallisation from pentane, m.p. about 80° C. (amorphous). R_(f) value(eluant: methylene chloride/methanol/conc. ammonia 60:10:1): 0.5.Crystallisation from ether.

The starting material may be prepared, for example, as follows:

a)(R)-3-(tert-Butoxycarbonylamino)-5-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one

Obtained analogously to the directions in Example 1a) starting from 4.8g of(R)-3-(tert-butoxycarbonyl-amino)-2,3-dihydro-1,5-benzoxazepin-4-one(prepared analogously to(S)-3-(tert-butoxycarbonylamino)-2,3-dihydro-1,5-benzoxazepin-4-one,starting from N-Boc-(D)-serine), 4.4 g of p-isopropylbenzyl chloride,2.9 g of potassium carbonate and 166 mg of potassium iodide. R_(f) value(eluant: hexane/ethyl acetate 4:1): 0.33.

b)(R)-3-Amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride

Obtained analogously to the directions in Example 1b) starting from 6.1g of(R)-3-(tert-butoxycarbonylamino)-2,3,4,5-tetrahydro-5-(p-isopropylbenzyl)-1,5-benzoxazepin-4-one.M.p. 214° C. (decomp.).

c)3-(R)-[(1-(S)-Ethoxycarbonyl-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine

Obtained analogously to the directions in Example 1c) starting from(R)-3-amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride, 2.93 g of(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethylester and 1.85 ml of N-methylmorpholine. Colourless resin, R_(f) value(eluant hexane/ethyl acetate 4:1): 0.36.

EXAMPLE 3

The following may be prepared in an analogous manner, for example asdescribed in Example 1 or 2:

3-(S)-[(1-(S)-carboxy-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. 200°;

3-(R)-[(1-(S)-carboxy-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 120°;

3-(R)-([1-(S)-carboxy-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-isobutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 160° (decomp.);

3-(R)-[(1-(S)-carboxy-isobutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-butyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 100°;

3-(R)-[(1-(S)-carboxy-butyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 145° (decomp.);

3-(S)-[(1-(R)-carboxy-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 130° (decomp.);

3-(S)-[(1-(S)-carboxy-isopentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 155° (decomp.);

3-(R)-[(1-(S)-carboxy-isopentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 166° (decomp.);

3-(S)-[(1-(R)-carboxy-2-cyclohexyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 100°;

3-(R)-[(1-(S)-carboxy-2-phenyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[1-(S)-carboxy-2-(p-methoxyphenyl)-ethyl]amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 110°;

3-(S)-[1-(R)-carboxy-2-(p-methoxyphenyl)-ethyl]amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 120°;

3-(S)-[1-(S)-carboxy-2-(p-fluorophenyl)-ethyl]amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 90°;

3-(R)-[1-(S)-carboxy-2-(p-fluorophenyl)-ethyl]amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenyl-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;m.p. of the hydrochloride: 191°-195°;

3-(R)-[(1-(S)-carboxy-3-phenyl-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine.

EXAMPLE 4

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinemay be prepared starting from 400 mg of3-(S)-[(1-(S)-ethoxycarbonyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepineby means of hydrolysis with dilute aqueous NaOH solution, m.p. 200° C.

The starting material may be prepared, for example, as follows:

3-(S)-[(1-(S)-ethoxycarbonyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine.

Obtained analogously to Example 1c) starting from 600 mg of(R)-3-amino-4-oxo-2,3,4,5-tetrahydro-5-(p-isopropylbenzyl)-1,5(5H)-benzoxazepinehydrochloride, 1.57 g of(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-propionic acid ethyl ester and0.76 ml of N-methylmorpholine. R_(f) value (eluant hexane/ethyl acetate2:1) 0.27.

(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-propionic acid ethyl ester wasobtained analogously to the sulfonic acid ester described in Example1c), starting from 10.3 g of D-lactic acid ethyl ester, 21.3 g of4-nitrobenzenesulfonyl chloride and 14.6 ml of triethylamine. R_(f)value (eluant hexane/ethyl acetate 2:1) 0.44.

EXAMPLE 5

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-3-methylbutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared starting from 650 mg of3-(S)-[(1-(S)-benzyloxycarbonyl-3-methylbutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepineby hydrogenation under normal pressure at room temperature in thepresence of 300 mg of palladium-on-carbon in 20 ml of dioxane (10%).After removal of the catalyst by filtration, the product is convertedinto the hydrochloride by treatment with 3.7N HCl in ethyl acetate. M.p.155° C. (decomp.).

The starting material may be prepared, for example, as follows:

15 g of D-leucine are placed in 172 ml of 1N aqueous sulfuric acid withcooling with an ice bath and, over a period of 1 hour, 11.8 g of sodiumnitrite in 45 ml of water are added thereto. The reaction solution isstirred overnight at room temperature, adjusted to pH=6 with sodiumhydrogen carbonate, concentrated to approximately 60 ml, and adjusted topH=3 with 40% phosphoric acid. The batch is extracted three times withtetrahydrofuran, and the organic phase is washed with brine, dried andconcentrated. The crude product is repeatedly concentrated byevaporation with toluene. Hexane is added to the residue, as a result ofwhich the product(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-methylvaleric acidprecipitates in the form of white crystals (m.p. 60°-62° C., afterdrying).

13.5 g of (R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-methylvaleric acidare heated at reflux for 6 hours with 42.1 ml of benzyl alcohol and 2.3ml of thionyl chloride using a water separator. After cooling, the darkyellow solution is concentrated by evaporation, taken up in ethylacetate, washed with brine, dried and concentrated. Distillation at118°-120° C./0.16 mbar yields the pure benzyl ester.

(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-2-(4-methylvaleric acid benzylester are obtained analogously to the sulfonic acid ester described inExample 1c) starting from 12.5 g of 2-(R)-hydroxy-5-valeric acid benzylester, 13.7 g of 4-nitrobenzenesulfonyl chloride and 9.4 ml oftriethylamine. R_(f) value (eluant hexane/ethyl acetate 2:1) 0.44. R_(f)value (eluant hexane/ethyl acetate 2:1) 0.46.

3-(S)-[(1-(S)-benzyloxycarbonyl-1-isobutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinewas obtained analogously to Example 1c) starting from 600 mg of(S)-3-amino-4-oxo-2,3,4,5-tetrahydro-5-(p-isopropylbenzyl)-1,5(5H)-benzoxazepinehydrochloride, 2.1 g of(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-methylvaleric acid benzylester and 0.76 ml of N-methylmorpholine. R_(f) value (eluanthexane/ethyl acetate 2:1) 0.56.

EXAMPLE 6

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-2-methylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared starting from 600 mg of3-(S)-[(1-(S)-benzyloxycarbonyl-1-isopropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepineby hydrogenation under normal pressure at room temperature in thepresence of 200 mg of palladium-on-carbon in 20 ml of dioxane (10%).After removal of the catalyst by filtration, the product is convertedinto the hydrochloride by treatment with 3.7N HCl in ethyl acetate. M.p.160° C. (decomp.).

The starting material may be prepared, for example, as follows:

3-(S)-[(1-(S)-Benzyloxycarbonyl-1-isobutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinewas obtained analogously to Example 1c) starting from 600 mg of(S)-3-amino-4-oxo-2,3,4,5-tetrahydro-5-(p-isopropylbenzyl)-1,5(5H)-benzoxazepinehydrochloride, 1.77 g of(R)-alpha-[[trifluoromethanesulfonyl]oxy]-3-methylbutyric acid benzylester (Tetrahedron 19, 6623, 1990) and 0.76 ml of N-methylmorpholine.R_(f) value (eluant hexane/ethyl acetate 4:1) 0.26.

EXAMPLE 7

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared starting from 520 mg of3-(S)-[(1-(S)-benzyloxycarbonyl-2-cyclohexylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepineby hydrogenation under normal pressure at room temperature withpalladium-on-carbon (10%) in 10 ml of dioxane. The product of thehydrogenation is converted into the hydrochloride by treatment with 5NHCl in ethyl acetate and dried. M.p. 166° C. (decomp.).

The starting material may be prepared analogously to Example 5 asfollows:

1.5 g of D-phenyllactic acid are hydrogenated under normal pressure for2 hours in the presence of 0.25 g of "Nishimura" catalyst (Rh₂ O₃ /PtO₂,Degussa) in 20 ml of methanol until saturation is achieved. Afterremoval of the catalyst by filtration followed by concentration, theproduct is obtained in the form of a yellow oil. R_(f) value (eluant:toluene/methylene chloride/ethyl acetate/formic acid 16:40:40:4) 0.52.

1.9 g of (R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-3-cyclohexylpropionicacid are heated at reflux for 20 hours using a water separator with 2.27ml of benzyl alcohol and 0.1 ml of thionyl chloride. After cooling, thedark yellow solution is concentrated by evaporation, taken up in ethylacetate, washed with brine, dried and concentrated Flash chromatography(eluant: petroleum ether/ethyl acetate 17:3) yields the pure product inthe form of a colourless resin. R_(f) value (eluant hexane/ethyl acetate4:1) 0.27.

(R)-alpha-[[(4-Nitrophenyl)sulfonyl]oxy]-3-cyclohexylpropionic acidbenzyl ester was obtained analogously to the sulfonic acid esterdescribed in Example 1c) starting from 1.9 g of2-(R)-3-cyclohexylpropionic acid benzyl ester, 1.8 g of4-nitrobenzenesulfonyl chloride and 1.21 ml of triethylamine. R_(f)value (eluant hexane/ethyl acetate 4:1) 0.41.

837 mgof(S)-3-amino-4-oxo-2,3,4,5-tetrahydro-5-(p-isopropylbenzyl)-1,5(5H)-benzoxazepinehydrochloride, 3.45 g of(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-3-cyclohexylpropionic acidbenzyl ester, 1.06 ml of N-methylmorpholine and 4 ml ofdimethylformamide are heated at 75° C. for 3 days. The reaction mixtureis concentrated and separated by means of flash chromatography (360 g ofsilica gel, eluant petroleum ether/ethyl acetate 4:1). The product isobtained in the form of a yellowish resin. R_(f) value (eluanthexane/ethyl acetate 4:1) 0.25.

EXAMPLE 8

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared, obtained analogously to Example 5 byhydrogenation of 0.41 g of3-(S)-[(1-(S)-benzyloxycarbonyl-2-phenylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinein the presence of 0.2 g of palladium-on-carbon (10%) in 10 ml ofdioxane. M.p. 100° C., R_(f) value (eluant methylenechloride/methanol/conc. ammonia 60:10:1) 0.23.

The starting material may be prepared analogously to Example 5, forexample as follows:

Starting from 11 g of D-phenyllactic acid benzyl ester, 10.5 g of4-nitrobenzenesulfonyl chloride and 6 ml of triethylamine,(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-3-phenylpropionic acid benzylester is obtained. R_(f) value (eluant ethyl acetate/hexane 1:4) 0.3.

Starting from 2.55 g of(R)-alpha-[[(4-nitrophenyl)sulfonyl]-oxy]-3-phenylpropionic acid benzylester, 800 mg of(R)-3-amino-4-oxo-2,3,4,5-tetrahydro-5-(p-isopropylbenzyl)-1,5(5H)-benzoxazepinehydrochloride and 0.88 ml of N-methylmorpholine,3-(S)-[(1-(S)-benzyloxycarbonyl-2-phenylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepineis obtained in the form of a yellow oil after flash chromatography (1 kgof silica gel, eluant petroleum ether/ethyl acetate 3:1). R_(f) value(eluant petroleum ether/ethyl acetate 3:1) 0.19.

EXAMPLE 9

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared, obtained analogously to Example 1 by thehydrolysis of3-(S)-[(1-(S)-ethoxycarbonyl-3-phenylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine.The preparation of the hydrochloride is carried out by treatment with 5NHCl in ethyl acetate. R_(f) value (eluant methylenechloride/methanol/conc. ammonia 60:10:1) 0.48.

The preparation of(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-phenylbutyric acid ethylester is described in Helv. Chim. Acta 71 (2), 337, 1988.

EXAMPLE 10

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinemay be prepared, obtained analogously to Example 8 by the hydrolysis of0.97 g of3-(S)-[(1-(S)-ethoxycarbonyl-3-phenylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinein 22 ml of ethanol, 10 ml of water and 1.55 g of NaOH. R_(f) value(eluant methylene chloride/methanol/conc. ammonia 60:10:1) 0.23. m.p.191°-192° C.

The starting material may be obtained, for example, as follows:

17 g of(S)-3-amino-4-oxo-2,3,4,5-tetrahydro-5-(p-isopropylbenzyl)-1,5(5H)-benzoxazepinehydrochloride, 48.2 g of(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-phenylbutyric acid ethylester and 19 ml of N-methylmorpholine are heated at 80° C. for 12 hours.After cooling, the batch is taken up in ethyl acetate, extracted withaqueous sodium hydrogen carbonate solution, dried and concentrated byevaporation. R_(f) value (eluant ethyl acetate/hexane 1:2) 0.34.

EXAMPLE 11

In an analogous manner, for examplc as described in Example 1,3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared, analogously to Example 1 by thehydrolysis of 29.2 g of3-(S)-[(1-(S)-ethoxycarbonyl-3-phenylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinein 150 ml of EtOH, 76 ml of 2N NaOH and 25 ml of Wasser. Thehydrochloride of the product is obtained by treatment with HCl inmethylene chloride. M.p. 124°-127° C.

The starting material may be obtained, for example, as follows:

Analogously to the directions in Example 1a), starting from 20 g of(S)-3-tert-butoxycarbonylamino-2,3-dihydro-1,5(5H)-benzoxazepin-4-one,15 g of p-methylbenzyl bromide and 9.67 g of potassium tert-butanolatein 120 ml of DMF,(S)-3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-5-(p-methylbenzyl)-1,5(5H)-benzoxazepin-4-oneis obtained. R_(f) value (eluant ethyl acetate/hexane 1:4) 0.28.

Analogously to the directions in Example 1b), starting from 2 g of(R)-3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-5-(p-methylbenzyl)-1,5(5H)-benzoxazepin-4-one,there is obtained by treatment with HCl in ethyl acetate (15 ml),(S)-3-amino-4-oxo-2,3,4,5-tetrahydro-5-(p-methylbenzyl)-1,5(5H)-benzoxazepinehydrochloride. After concentration of the reaction mixture byevaporation the residue is triturated with ether, by means of which theproduct is obtained in the form of a beige powder. R_(f) value (eluantmethylene chloride/MeOH 95:5) 0.3.

3-(S)-[(1-(S)-ethoxycarbonyl-3-cyclohexylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepineis obtained analogously to the directions in Example 1c), starting from20 g of(S)-3-amino-4-oxo-2,3,4,5-tetrahydro-5-(p-methylbenzyl)-1,5(5H)-benzoxazepinehydrochloride, 37.6 g of(R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethylester and 8.6 ml of N-methylmorpholine. The product is obtained in theform of a beige powder after trituration with petroleumether/methyl-tert-butyl ether (7:1) at -78° C. R_(f) value (eluantpetroleum ether/ethyl acetate 4:1) 0.19.

EXAMPLE 22

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared, m.p. 120° C., R_(f) value (eluantmethylene chloride/methanol/conc. ammonia 60:10:1) 0.23, analogously toExample 5 starting from D-2-aminobutyric acid.

EXAMPLE 13

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-butyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared, m.p. 100° C., R_(f) value (eluantmethylene chloride/methanol/conc. ammonia 60:10:1) 0.27; analogously toExample 5 starting from D-norvaline.

EXAMPLE 14

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride and3-(S)-[(1-(R)-carboxy-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared.

1-(S)-isomer: m.p. 145° C., R_(f) value (eluant methylenechloride/methanol/conc. ammonia 60:10:1) 0.25. Obtained by hydrolysis ofthe more polar ethyl ester; 1-(R)-isomer: m.p. 130° C. (decomp.).Obtained by hydrolysis of the less polar ethyl ester; analogously toExample 5 starting from D,L-2-hydroxycaproic acid ethyl ester. The twodiastereoisomers are separated by flash chromatography at the3-(S)-[(1-(S)-ethoxycarbonyl-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinestage. R_(f) values (eluant ethyl acetate/petroleum ether 15:85) 0.33and 0.23.

EXAMPLE 15

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-2-(p-methoxyphenyl)ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride and3-(S)-[(1-(R)-carboxy-2-(p-methoxyphenyl)ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared.

1-(S)-isomer: m.p. 120° C., R_(f) value (eluant methylenechloride/methanol/conc. ammonia 60:10:1) 0.22. By hydrolysis Of the lesspolar methyl ester. 1-(R)-isomer: m.p. 110° C., R_(f) value (eluantmethylene chloride/methanol/conc. ammonia 60:10:1) 0.18. By hydrolysisof the more polar methyl ester; analogously to Example 5 starting fromD,L-p-methoxyphenylalanine. The two diastereoisomers are separated byflash chromatography at the3-(S)-[(1-(R/S)-methoxycarbonyl-2-(p-methoxyphenyl)ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinestage. R_(f) values (eluant ethyl acetate/petroleum ether 4) 0.3 and0.28.

EXAMPLE 16

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-2-(p-fluorophenyl)ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared, m.p. 90° C., R_(f) value (eluantmethylene chloride/methanol/conc. ammonia 60:10:1) 0.24; analogously toExample 5 starting from D-p-fluorophenylalanine.

EXAMPLE 17

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-2-benzyloxy-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinemay be prepared, m.p. 178°-182° C.; analogously to Example 5 startingfrom D-benzylserine.

EXAMPLE 18

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinemay be prepared, m.p. 191°-195° C.

EXAMPLE 19

In an analogous manner, for example as described in Example 1,3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(m-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepinehydrochloride may be prepared, R_(f) value (eluant methylenechloride/methanol/conc. ammonia 60:10:1) 0.48, analogously to Example 1starting from m-methylbenzyl chloride.

EXAMPLE 20

The following may be prepared in an analogous manner, for example asdescribed in one of the preceding Examples:

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-aminobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-dimethyl-aminobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-tert-butylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-methoxybenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-ethylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-fluorobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-chlorobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-bromobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-iodobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-aminobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-dimethylaminobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-tert-butylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-methoxybenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-ethylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-fluorobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-chlorobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-bromobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-iodobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-aminobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-dimethylaminobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-tert-butylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-methoxybenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-ethylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-fluorobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-chlorobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-bromobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-iodobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-aminobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-dimethylaminobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-tert-butylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-methoxybenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-ethylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-fluorobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-chlorobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-bromobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-iodobenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carbamoyl-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carbamoyl-3-phenylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carbamoyl-2-phenylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carbamoyl-2-cyclohexylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carbamoyl-3-cyclohexylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carbamoyl-3-phenyl)propylamino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carbamoyl-2-phenylethyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-carbamoyl-2-cyclohexylethyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-N-hydroxy-carbamoyl-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-N-hydroxy-carbamoyl-3-phenylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-N-hydroxy-carbamoyl-2-phenylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-N-hydroxy-carbamoyl-2-cyclohexylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-N-hydroxy-carbamoyl-3-cyclohexylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-N-hydroxy-carbamoyl-3-phenylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-N-hydroxy-carbamoyl-2-phenylethyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

3-(S)-[(1-(S)-N-hydroxy-carbamoyl-2-cyclohexylethyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;

EXAMPLE 21

Tablets, each comprising 50 mg of active ingredient, e.g.3-(S)-[(1-(S)-carboxy-3-cyclohexyl-propyl)-amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine,may be prepared as follows:

    ______________________________________                                        Composition (for 10 000 tablets):                                             ______________________________________                                        active ingredient        500.0  g                                             lactose                  500.0  g                                             potato starch            352.0  g                                             gelatin                  8.0    g                                             talc                     60.0   g                                             magnesium stearate       10.0   g                                             silicon dioxide (highly dispersed)                                                                     20.0   g                                             ethanol                  q.s.                                                 ______________________________________                                    

The active ingredient is mixed with the lactose and 292 g of potatostarch and the mixture is moistened with an alcoholic solution of thegelatin and granulated through a sieve. After drying the granules, theremainder of the potato starch, the talc, the magnesium stearate and thehighly dispersed silicon dioxide are added thereto and the mixture iscompressed to form tablets, each weighing 145.0 mg and comprising 50.0mg of active ingredient, which may, if desired, be provided withbreaking notches for the purpose of finer adjustment of the dose.

EXAMPLE 22

Film-coated tablets, each comprising 100 mg of active ingredient, e.g.3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine,may be prepared as follows:

    ______________________________________                                        Composition (for 1000 tablets):                                               ______________________________________                                        active ingredient       100.00  g                                             lactose                 100.00  g                                             corn starch             70.00   g                                             talc                    8.50    g                                             calcium stearate        1.50    g                                             hydroxypropylmethylcellulose                                                                          2.36    g                                             shellac                 0.64    g                                             water                   q.s.                                                  dichloromethane         q.s.                                                  ______________________________________                                    

The active ingredient, the lactose and 40 g of the corn starch are mixedand moistened with a paste prepared from 15 g of corn starch and water(with heating) and granulated. The granules are dried, and the remainderof the corn starch, the talc and the calcium stearate are added andmixed with the granules. The mixture is compressed to form tablets(weight: 280 mg) which are then film-coated with a solution of thehydroxypropylmethylcellulose and the shellac in dichloromethane (finalweight of the film-coated tablet: 283 mg).

EXAMPLE 23

In an analogous manner, for example as described in Examples 20 and 21,it is also possible to prepare tablets and film-coated tabletscomprising a different compound of formula I or a pharmaceuticallyacceptable salt of a compound of formula I, e.g. according to any one ofExamples 1 to 20.

We claim:
 1. A 3-amino-1-arylalkyl-benzazepin-2-one of the generalformula ##STR18## wherein Ar is selected from the group consisting ofphenyl, naphthyl, monocyclic, monoza-, monooxa-, monothia-, diaza-,oxaza- and thiaza-aryl;X is --O-- or --S(O)_(n) and n is 0, 1 or 2; X₁is C₁ -C₂ alkylene or a direct bond; R₁ is hydrogen, lower alkyl,pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl, thiazolyllower alkanoyl, aroyl, or benzoyl; R₂ is lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, pyrrolyl, pyridyl, furyl, thienyl,imidazolyl, isoxazolyl, thiazolyl or C₃ -C₇ cycloalkyll-lower alkyl; R₃is carboxy; lower alkoxycarbonyl; lower alkoxy-lower alkoxycarbonyl;pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl, thiazolyl;carbamoyl; carbamoyl that (I) is monosubstituted or disubstituted, thesubstituents being independent of one another, by lower alkyl, loweralkenyl, lower alkynyl or by phenyl-lower alkyl or (iii) isdisubstituted by lower alkylene or by lower alkylene-Z₁ -lower alkylene,Z₁ being O, S or NH; 5-tetrazolyl; Po₂ H₂ ; PO₃ H₂ or SO₃ H₂ ; the ringA and aromatic radicals are, independently of one another, unsubstitutedor mono- or poly-substituted by substituents selected from the groupconsisting of: lower alkyl, pyrrolyl, pyridyl, furyl, thienyl,imidazolyl, isoxazolyl, thiazolyl, lower alkoxy-lower alkyl, loweralkoxy, lower alkoxy-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇cycloalkyl-lower alkyl, nitrol, halogen, trifluoromethyl, amino andamino that is monosubstituted or disubstituted, the substituents beingindependent of one another, by lower alkyl, pyrrolyl, pyridyl, furyl,thienyl, imidazolyl, isoxazolyl, thiazolyl or by phenyl, naphthyl,monocyclic, monoza-, monooxa-, monothia-, diaza-, oxaza- andthiaza-aryl, or disubstituted by lower alkylene or by loweralkyleneoxy-lower alkylene; a steroisomer or a salt thereof.
 2. Acompound according to claim 1 of formula I whereinAr is phenyl; X is--O-- or --S(O)_(n) -- and n is 0, 1 or 2; X₁ is C₁ -C₂ alkylene or adirect bond; R₁ is hydrogen, lower alkyl, lower alkyl that issubstituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl, thienyl,imidazolyl, isoxazolyl or by thiazolyl, lower alkanoyl, lower alkanoylthat is substituted by phenyl, naphthyl, pyrrolyl, pyridyl, furyl,thienyl, imidazolyl, isoxazolyl or by thiazolyl, or benzoyl; R₂ is (i)lower alkyl, lower alkyl that is substituted by phenyl, naphthyl,pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or bythiazolyl, or C₁ -C₇ cycloalkyl-lower alkyl, or (ii) hydroxy-loweralkyl, lower alkoxy-lower alkyl, or lower alkoxy-lower alkyl in whichthe lower alkoxy moiety is substituted by phenyl, naphthyl, pyrrolyl,pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or by thiazolyl; R₃ is(i) carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ or SO₃ H₂ or (ii) loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, phenyl-loweralkoxycarbonyl, benzoylcarbonyl, carbamoyl, lower alkylcarbamoyl,di-lower alkylcarbamoyl, phenyl-lower alkylcarbamoyl, diphenyl-loweralkylcarbamoyl, hydroxycarbamoyl, lower alkanesulfonyl-carbamoyl,halo-lower alkanesulfonyl or phenylsulfonyl; the ring A and aromaticradicals are, independently of one another, unsubstituted or mono- orpoly-substituted by substituents selected from the group consisting of:lower alkyl, lower alkyl that is substituted by phenyl, naphthyl,pyrrolyl, pyridyl, furyl, thienyl, imidazolyl, isoxazolyl or bythiazolyl, lower alkoxy-lower alkyl, lower alkoxy, lower alkoxy-loweralkoxy, phenyl-lower alkoxy, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl-loweralkyl, nitro, halogen, trifluoromethyl, amino and amino that ismonosubstituted or disubstituted, the substituents being independent ofone another, by lower alkyl, phenyl-lower alkyl or by phenyl ordisubstituted by lower alkylene or by lower alkyleneoxy-lower alkylene;a stereoisomer or a salt thereof.
 3. A compound according to claim 1 offormula I whereinAr is phenyl; X is --O-- or --S(O)_(n) -- and n is 0, 1or 2; X₁ is C₁ -C₂ alkylene or a direct bond; R₁ is hydrogen, loweralkyl, phenyl-lower alkyl, lower alkanoyl, phenyl-lower alkanoyl orbenzoyl; R₂ is lower alkyl, phenyl-lower alkyl or C₃ -C₇cycloalkyl-lower alkyl; R₃ is (i) carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂or SO₃ H₂ or (ii) carbamoyl or hydroxy-carbamoyl; the ring A andaromatic radicals are, independently of one another, unsubstituted ormono- or poly-substituted by substituents selected from the groupconsisting of: lower alkyl, phenyl-lower alkyl, lower alkoxy-loweralkyl, lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, C₃-C₇ cycloalkyl, C₃ -C₇ cycloalkyl-lower alkyl, nitro, halogen,trifluoromethyl, amino and amino that is monosubstituted ordisubstituted, the substituents being independent of one another, bylower alkyl, phenyl-lower alkyl or by phenyl, or disubstituted by loweralkylene or by lower alkyleneoxy-lower alkylene; a stereoisomer or asalt thereof.
 4. A compound according to claim 1 of formula I whereinAris phenyl or phenyl substituted by C₁ -C₄ alkyl; X is --O-- or--S(O)_(n) -- and n is 0, 1 or 2; X₁ is C₁ -C₂ alkylene or a directbond; R₁ is hydrogen, C₁ -C₄ alkyl or C₂ -C₅ alkanoyl; R₂ is phenyl-C₁-C₄ alkyl wherein phenyl is unsubstituted or is substituted by halogen,trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄ alkoxy, or R₂ is C₃ -C₇cycloalkyl-C₁ -C₄ alkyl; R₃ is carboxy, 5-tetrazolyl, PO₂ H₂, PO₃ H₂ orSO₃ H₂ ; the ring A is unsubstituted or mono- or poly-substituted bysubstituents selected from the group consisting of:C₁ -C₄ alkyl,halogen, C₃ -C₇ alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkoxy-C₁ -C₄alkoxy, nitro, halogen and trifluoromethyl; a stereoisomer or a saltthereof.
 5. A compound according to claim 1 of formula I whereinAr isphenyl substituted by C₁ -C₄ alkyl, lower alkoxy, halogen,trifluoromethyl, amino, lower alkylamino, di-lower alkylamino or bynitro; X is --O--; X₁ is methylene; R₁ is hydrogen or C₂ -C₅ alkanoyl;R₂ is phenyl-C₁ -C₄ alkyl wherein phenyl is unsubstituted or issubstituted by halogen, trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄alkoxy; or R₂ is C₃ -C₇ cycloalkyl-C₁ -C₄ alkyl; R₃ is carboxy,carbamoyl or hydroxycarbamoyl; the ring A is unsubstituted or mono- orpoly-substituted by substituents selected from the group consistingof:C₁ -C₄ alkyl, halogen, C₁ -C₄ alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁-C₄ alkoxy-C₁ -C₄ alkoxy, nitro, halogen and trifluoromethyl; astereoisomer or a salt thereof.
 6. A compound according to claim 1 offormula I whereinAr is phenyl or phenyl substituted by C₁ -C₄ alkyl; Xis --O--; X₁ is methylene; R₁ is hydrogen or C₂ -C₅ alkanoyl; R₂ isphenyl-C₁ -C₄ alkyl wherein phenyl is unsubstituted or is substituted byhalogen, trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄ alkoxy; or R₂ is C₃-C₇ cycloalkyl-C₁ -C₄ alkyl; R₃ is carboxy or 5-tetrazolyl; the ring Ais unsubstituted or is mono- or poly-substituted by substituentsselected from the group consisting of:C₁ -C₄ alkyl, halogen, C₁ -C₄alkoxy-C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkoxy-C₁ -C₄ alkoxy, nitro,halogen and trifluoromethyl; a stereoisomer or a salt thereof.
 7. Acompound according to claim 1 of formula ##STR19## wherein R₁ ishydrogen; R₂ is phenyl-C₁ -C₄ alkyl wherein phenyl is unsubstituted oris substituted by halogen, trifluoromethyl, C₁ -C₄ alkyl or by C₁ -C₄alkoxy, or R₂ is C₅ -C₆ cycloalkyl-C₁ -C₄ alkyl; R₃ is carboxy; and R₄is C₁ -C₄ alkyl; a stereoisomer or a salt thereof.
 8. A compoundaccording to claim 1 of formula ##STR20## wherein R₁ is hydrogen; R₂ isphenyl-C₁ -C₄ alkyl or C₅ -C₆ cycloalkyl-C₁ -C₄ alkyl; R₃ is carboxy;andR₄ is C₁ -C₄ alkyl; a stereoisomer or a salt thereof.
 9. A compoundaccording to claim 1 of formulae I wherein both the carbon atom havingthe variables R₂ and R₃, and the carbon atom to which the amino group isbonded, have the (S)-configuration.
 10. A compound selectedfrom3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;-3(S)-[(1-(S)-carboxy-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-[(1-(S)-carboxy-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-([1-(S)-carboxy-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-isobutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-[(1-(S)-carboxy-isobutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-butyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-[(1-(S)-carboxy-butyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(R)-carboxy-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-isopentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-[(1-(S)-carboxy-isopentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-2-cyclohexyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(R)-carboxy-2-cyclohexyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-2-phenyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-[(1-(S)-carboxy-2-phenyl-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[1-(S)-carboxy-2-(p-methoxyphenyl)-ethyl]amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[1-(R)-carboxy-2-(p-methoxyphenyl)-ethyl]amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[1-(S)-carboxy-2-(p-fluorophenyl)-ethyl]amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-[1-(S)-carboxy-2-(p-fluorophenyl)-ethyl]amino-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-3-phenyl-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(R)-[(1-(S)-carboxy-3-phenyl-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;or a salt thereof.
 11. A compound selectedfrom3-(S)-[(1-(S)-carboxy-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-3-methylbutyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-2-methylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-2-cyclohexylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-2-phenylethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-3-cyclohexylpropyl)amino]-5-(p-methylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-propyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-butyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(R)-carboxy-pentyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-2-(p-methoxyphenyl)ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(R)-carboxy-2-(p-methoxyphenyl)ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-2-(p-fluorophenyl)ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-2-benzyloxy-ethyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(p-isopropylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;and3-(S)-[(1-(S)-carboxy-3-phenylpropyl)amino]-5-(m-methylylbenzyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine;or a salt thereof in each case.
 12. A process for the preparation of acompound of formula I, a stereoisomer or a salt thereof, whichcomprisesa) in a compound of formula ##STR21## wherein Y₁ is a radicalthat can be converted into the variable R₃, or in a salt thereof,converting Y₁ into the variable R₃ ; or, b) for the preparation of acompound of formula (I) wherein R₁ is hydrogen, or for the preparationof a salt thereof, a compound of formula ##STR22## wherein Y₂ is anamino-protecting group, or in a salt thereof, removing theamino-protecting group; or c) reacting a compound of formula ##STR23##with a compound of formula ##STR24## (IVb), wherein Y₄ is a nucleofugalleaving group, or with a compound of formula R₂ --CO--R₃ (IVc) or a saltthereof; or d) reacting a compound of formula ##STR25## with a compoundof formula Y₆ --X₁ --Ar (Vb), wherein Y₆ is a nucleofugal leaving group,or with a salt thereof; or e) reacting a compound of formula ##STR26##wherein Y₇ is (i) oxo or (ii) reactive esterified hydroxy together withhydrogen, with a compound of formula ##STR27## (VIb) or with a saltthereof; and in each case, if desired, isolating in free form or in saltform a compound of formula I obtainable according to the process or insome other manner, converting a compound of formula I obtainableaccording to the process or in some other manner into a differentcompound of formula I, separating a mixture of isomers obtainableaccording to the process and isolating the desired isomer and/orconverting a free compound of formula I obtainable according to theprocess into a salt or a salt of a compound of formula I obtainableaccording to the process into the free compound of formula I or into adifferent salt.
 13. A pharmaceutical composition for treatingpathological symptoms of the human body that are brought about bymodulation of the AT₂ -receptor comprising as active ingredient acompound according to claim 1, a stereoisomer or a pharmaceuticallyacceptable salt thereof, where appropriate together with customaryexcipients.
 14. A method of treating pathological symptoms of the humanbody that are brought about by modulation of the AT₂ -receptor, whichcomprises administering a therapeutically effective amount of a compoundof formula I according to claim 1, or of a stereoisomer orpharmaceutically acceptable salt thereof.
 15. A method of stimulatinggrowth-inhibiting and antiproliferative effects of tyrosine phosphatasecomprising administering a therapeutically effective amount of acompound according to claim 1, or of a stereoisomer or apharmaceutically acceptable salt thereof.
 16. A method of treatingvascular proliferation disorders comprising administering atherapeutically effective amount of a compound according to claim 1, orof a stereoisomer or a pharmaceutically acceptable salt thereof.
 17. Amethod of treating sterility dysfunction caused by anovulation,ovulation disorders, dysfunction of the corpus luteum and missedabortion comprising administering a therapeutically effective amount ofa compound according to claim 1, or of a stereoisomer or apharmaceutically acceptable salt thereof.
 18. A method of treatingdysmenorrhoea comprising administering a therapeutically effectiveamount of a compound according to claim 1, or of a stereoisomer or apharmaceutically acceptable salt thereof.